A major increase in research activities is proposed for the University of Washington's Alzheimer's Disease Research Center, which serves the WAMI region of the Pacific Northwest (Washington, Alaska, Montana, Idaho). A focus on familial forms of Alzheimer's disease continues, with a proposed expansion of the pace of research of the centerpiece project dealing with linkage analysis, particularly on early onset forms of the disorder and the first subset of pedigrees for which there is evidence of a genetic founder effect (the "Volga German" families). The research now includes a collaborative effort with Duke University ADRC, which will provide additional early onset pedigrees. Five new projects have been added, dealing with: the nature of the CNS noradrenergic abnormality: the pathogenetic role of proteoglycans; functional and biochemical studies of the role of the microtubule associated protein, tau; the assessment of levels of CSF nerve growth factor as functions of aging and dementia; studies of biased hypermutation (uridine to cytidine transitions) of viral and cellular RNA molecules in neural cells. Feasibility studies have been increased from 2 per year to 4-6 per year, including new proposals on neuromodulin, somatostatin, K+ channel gene expression, mitochondrial DNA,k retroviral-mediated neural chimeras, yeast artificial chromosomes for the bioassay of relevant gene action, and studies of NMDA receptors by PET. These various studies are unified by a concern with pathogenetic mechanisms. In addition to the continuing interest in autosomal dominant gene action, several studies address the role of trisomy 21 n the pathogenesis. The original 5 Core Units have been continued (Administration; Research Training & Information Transfer; Clinical/Data Management & Biostatistics; Autopsy/Neuropathology; Cell Culture/Cell Bank/Cytogenetics), including a major expansion of the educational activities.